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SU2C-OCRFA-NOCC Ovarian Cancer Dream Team Progress Update

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SU2C-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Progress Report

DNA Repair Therapies for Ovarian Cancer

Funding: $6,000,000

Leader: Alan D. D’Andrea, MD, Dana-Farber Cancer Institute
Co-Leader: Elizabeth M. Swisher, MD, University of Washington

Principals: Gini F. Fleming, MD, The University of Chicago
Scott H. Kaufmann, MD, PhD, Mayo Clinic
Maria Jasin, PhD, Memorial Sloan Kettering Cancer Center
Karen H. Lu, MD, UT MD Anderson Cancer Center

Advocates: Jamie Crase, ovarian cancer survivor and advocate
Kathleen A. Gavin, Minnesota Ovarian Cancer Alliance; Member, NRG Oncology Committees
Sue Friedman, Executive Director, FORCE (Facing Our Risk of Cancer Empowered)

Fast Facts on Ovarian Cancer:

  • Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system
  • Less than half of women diagnosed with ovarian cancer survive to five years or more
  • Ovarian cancer develops mainly in older women and is more common in white women than African-American women

Fast Facts on Ovarian Cancer Prevention:

  • Ovarian cancer can be inherited. Talk to your doctor about reducing your risk if there is a history of ovarian cancer in the women in your family.
  • Hormonal contraceptives, first full-term pregnancy before age 26, and breast feeding may lower the risk of ovarian cancer.
  • Maintain a healthy diet and avoid obesity.


Summary
Ovarian cancer is usually diagnosed at an advanced stage and, despite good initial responses to treatment, recurrence is very common. Because of this, cure is unlikely, and the death rate is high. Progress toward new treatments has been slow. However, new information from genetic sequencing of high-grade serous ovarian cancers has revealed a common weakness - mutations that cause defects in biological pathways that repair damaged DNA. Cancers with certain types of DNA repair defects are responsive to specific targeted therapies, such as drugs called PARP inhibitors, one of which was recently approved by the Food and Drug Administration to treat ovarian cancers associated with mutations in the BRCA1 and BRCA2 DNA repair genes.

SU2C-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team aims to develop new therapies that target DNA repair, and to expand PARP inhibitor use to a much larger group of women, beyond those with BRCA1 and BRCA2 mutations. In addition, by screening for inherited mutations in DNA repair genes, the Dream Team hopes to identify women at high risk for ovarian cancer for whom preventative measures may be life-saving.

The Dream Team brings together existing expertise from DNA repair experts, translational investigators, and clinicians, across six institutions, to create new programs in discovery, translation, and clinical application, while cross-fertilizing and educating researchers at all levels to enhance collaboration and catalyze translational science. Their three-pronged approach will 1) apply cutting edge DNA repair science to identify ovarian cancers most likely to respond to DNA repair therapies; 2) evaluate, in three clinical trials, novel drug combinations that will sensitize ovarian tumors to PARP inhibitors thereby expanding the use of these drugs to more women; and 3) develop web-based genetic testing and counselling strategies for ovarian cancer risk, providing access to more women in the community, and test fallopian tube removal as a surgical approach to reduce risk that will avoid forced menopause by preserving a woman’s ovaries.

With a combined focus on developing and expanding treatment options, as well as developing platforms for the identification of women at high risk for ovarian cancer and preventing their disease, this program is poised to quickly deliver near-term ovarian cancer patient benefit.

 

Status update

6 months:
In the first 6 months of this grant, the team has made considerable progress in all aspects of the project.

  • The Team has rapidly established a strong collaborative infrastructure between the groups who will work on the different Aims. They are working to establish standardized review of tumor material by the Team’s pathologists so that they optimize the use of information from different trial sites.
  • The Team has started analyzing DNA sequencing data from ovarian tumor biopsies from patients enrolled in an ongoing PARP inhibitor clinical trial. They are finding clues as to the genetic changes that associate with sensitivity to the PARP inhibitor rucaparib in women without BRCA mutations. This approach may allow them to predict who will respond to these drugs. Dr. Swisher, the Dream Team co-leader, presented these preliminary results at the AACR Ovarian Cancer Symposium in October 2015.
  • The Dream Team has started laboratory studies and analyses of clinical trial samples to understand the biology of why some patients may not respond to certain therapies.
  • Two clinical trials are actively recruiting ovarian cancer patients to evaluate new drug combinations. Additional trials are pending activation.
  • They acted quickly on the suggestions of the Joint Scientific Advisory Committee to incorporate an immunotherapy focus to their work. In collaboration with Merck/Tesaro, they are planning a new clinical trial to test an immunotherapy drug Pembrolizumab (Keytruda®), currently approved for use in metastatic melanoma and a type of lung cancer, in combination with a PARP inhibitor Niraparib.
  • Development of the Dream Team’s genetic testing trial, now named MAGENTA (MAking GENetic Testing more Accessible), and their prevention trial WISDOM (Women choosing Interval Salpingectomy with Delayed Oophorectomy to postpone Menopause) continues. The MAGENTA trial seeks to increase access to genetic testing for ovarian cancer risk in the community by using online genetic counseling. Based on the growing understanding that ovarian cancer may start in the fallopian tubes, the WISDOM trial will offer women at high risk of ovarian cancer the option to remove their fallopian tubes as an approach to reduce their risk while avoiding forced menopause by preserving a their ovaries.

12 months:
In the 7-12 month period of this grant, this Dream Team continues to make significant progress in all research areas.

  • The Team has identified two ways by which patients may be resistant to PARP inhibitor treatment. Understanding why some patients stop responding to PARP inhibitors will provide insight into potential drug combinations to overcome resistance.
  • The Team has identified a potential “biomarker” or biological signal that may be used to predict how well a patient’s tumor will response to treatment with a PARP inhibitor.
  • The Team has identified the best dose strategies to use in two different combination clinical trials and forges forward with recruiting patients to analyze their tumors with or without the combination treatment.
  • The genetic testing clinical trial, MAGENTA, has been revised and is not yet open.
  • The surgical prevention clinical trial was renamed to WISP (women choosing surgical prevention) and will start enrolling patients in the summer/early fall of 2016.

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